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1 Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Korea, Republic of
* To whom correspondence should be addressed. E-mail: gykoh{at}postech.ac.kr.
To clarify the role of caveolae in vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2)-mediated signaling cascades, primary cultured human umbilical
vein endothelial cells (HUVECs) were fractionated to isolate caveolae-enriched cell membranes. Interestingly, VEGFR-2, phospholipase D2 (PLD2), and Ras were enriched
in caveolae-enriched fractions. Moreover, VEGF increased PLD activity in a time- and dose-dependent manner in HUVECs, while a ligand specific for VEGFR-1, placenta
growth factor, did not change PLD activity. A PLD inhibitor, 1-butanol almost completely suppressed VEGF-induced ERK phosphorylation and cellular proliferation,
while the negative control for 1-butanol, 3-butanol, did not produce significant changes. Addition of phosphatidic acid negated the 1-butanol-induced suppression.
Pharmacological analyses using several inhibitors indicated that protein kinase C-
(PKC- ) regulates the VEGF-induced activation of PLD/ERK. Thus, PLD2 could be involved in MEK/ERK signaling cascades that are induced by the VEGF/VEGFR- 2/PKC- pathway in endothelial cells. Pretreatment with the cholesterol depletion agent
methyl-
-cyclodextrin (M CD) almost completely disassembled caveolar structures, while addition of cholesterol to M CD-treated cells restored caveolar structures. Pretreatment with M CD largely abolished phosphorylation of MEK/ERK by VEGF, while addition of cholesterol restored VEGF-induced MEK/ERK phosphorylations. These results indicate that intact caveolae are required for the VEGF/VEGFR-2 mediated MEK/ERK signaling cascade.
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